The present invention relates to cyclic amine derivatives and use thereof. These derivatives are useful for pharmaceutical compositions such as an antiobestic agent and a preventive or therapeutic agent for diabetes.
Nowadays, while dietary life is rich and living environment becomes convenient, the patients of obesity keep on increasing. Along with the increase thereof, other various circulatory system diseases such as diabetes, hypertension and hyperlipemia are also spreading as life habit diseases. As the basic therapy for obesity, the diet therapy and the functional therapy have been adopted. When their therapy are not so effective or the patients are of excessive obesity type, the medical therapy, administering a feeding deterrent agent such as 5-HT antagonist, has been conducted. However, the feeding deterrent agent can not essentially improve the obese physical constitution because it does not decompose lipid in obese cells. Moreover, when the feeding deterrent agent is administered to patients so as to excessively repress the appetite of patients, the amount of nutrition-intake in the daily life decreases to less than the minimum level to lead the health control problem. Further, since the feeding deterrent agent acts on the central nervous system, side effects to brain are concerned. Therefore, the feeding deterrent agent is usually used as a supplement in the basic therapy. On the other hand, the pharmacological effect of leptin, a protein produced by an obese gene, had been considered as feeding deterrent effect in the beginning of the research. However, the recent study has revealed that the main effect is the acceleration of lipid decomposition by fever production in fat cells. Namely, it is expected that the stimulation of leptin-release leads to the essential treatment of obesity. (Halaas, J. L., et al. (1995) Weight-reducing effects of the blood protein encoded by the obese gene. Science, 269: 543-546).
Further, diabetes mellitus is usually classified into two types: insulin-dependence (type I , IDDM) accompanied with the decrease of insulin-producing cells and non insulin-dependence (type II, NIDDM) which is considered to be generated by the decrease of insulin sensibility. As the clinical situation, 90% or more of the diabetes mellitus patients are involved in the latter. In the non insulin-dependence diabetes mellitus (type II diabetes mellitus), while the concentration of insulin in blood is high, the sensibility of somatic cells to insulin is decreased due to insulin-resistance. Thus, the intake of glucose existing in blood into somatic cells is inhibited. As the therapeutic agent for type II diabetes mellitus which can improve the insulin resistance, thiazolidine derivatives and the like are under development.
In J. Pharm. Pharmacol. 1962, 14, 16, some tetrahydropyridine derivatives are described as possessing an anti-hypertensive effect without any other use disclosed.
Therefore, it has been desired to develop a novel antiobestic agent, preferably, which can be safely used without the excessive feeding deterrent. Further needed is a novel preventive or therapeutic agent for diabetes mellitus, especially type II diabetes mellitus, which is one of the diseases associated with obesity.
The present inventors have intensively studied to find out that cyclic amine derivatives have various pharmacological effects such as reducing body weight, lowering the concentration of insulin and glucose in blood and/or increasing the concentration of leptin in blood and so they are for use as a preventive or therapeutic agent for obesty and/or diabetes and the like, whereby accomplishing the present invention shown below.
(1) A composition for use as an antiobestic agent, containing a compound of the formula (I): 
wherein A is optionally substituted aryl or optionally substituted heteroaryl; X is O, S, N R wherein R is hydrogen or lower alkyl, or a single bond;
m is an integer of 0 to 4;
n is an integer of 1 to 5;
p is an integer of 1 to 3, pharmaceutically acceptable salt, prodrug or hydrate thereof.
(2) The composition for use as an antiobestic agent described in above (1) containing a compound wherein A is optionally substituted phenyl, optionally substituted pyridyl, optionally substituted isoquinolyl, optionally substituted quinolyl, optionally substituted thienyl, optionally substituted furyl, optionally substituted benzothienyl, or optionally substituted benzofuryl.
(3) The composition for use as an antiobestic agent described in above (1) containing a compound wherein A is optionally substituted phenyl or optionally substituted benzothienyl.
(4) The composition for use as an antiobestic agent described in above (1) containing a compound wherein A is phenyl substituted with same or different, one to three group(s) selected from the group consisting of halogen, hydroxy, lower alkyl, halogenated lower alkyl, piperidyl (lower) alkyl, lower alkoxy, halogenated lower alkoxy, carboxy lower alkoxy, optionally substituted aryl, optionally substituted aryloxy and optionally substituted aryl (lower) alkoxy.
(5) The composition for use as an antiobestic agent described in above (1) containing a compound wherein X is O or NR wherein R is methyl or ethyl.
(6) The composition for use as an antiobestic agent described in above (1) containing a compound wherein X is O.
(7) The composition for use as an antiobestic agent described in above (1) containing a compound wherein m is 0.
(8) The composition for use as an antiobestic agent described in above (1) containing a compound wherein n is 2 or 3.
(9) The composition for use as an antiobestic agent described in above (1) containing a compound wherein p is 2.
(10) The composition for use as an antiobestic agent described in above (1) containing a compound wherein A is optionally substituted phenyl or optionally substituted benzothienyl; X is O or NR wherein R is methyl or ethyl; m is 0; n is 2 or 3; and p is 2.
(11) The composition for use as an antiobestic agent described in above (1) containing a compound wherein A is optionally substituted phenyl; X is O; m is 0; n is 2 or 3; and p is 2.
(12) A composition for use as a preventive or therapeutic agent for diabetes containing a compound described in any one of above (1) to (11).
(13) A composition for use as an agent for increasing concentration of leptin in blood containing a compound described in any one of above (1) to (11).
(14) A compound of the formula (II): 
wherein B is 
wherein R1, R2 and R3 are each independently hydrogen, halogen, hydroxy, lower alkyl, halogenated lower alkyl, piperidyl (lower) alkyl, lower alkoxy, halogenated lower alkoxy, carboxy lower alkoxy, optionally substituted aryl, optionally substituted aryloxy, or optionally substituted aryl (lower) alkoxy; Z1 is CH or N; Z2 is O or S;
X is O, S, NR wherein R is hydrogen or lower alkyl, or a single bond;
m is an integer of 0 to 4;
n is an integer of 1 to 5;
p is an integer of 1 to 3,
provided that when B is (a), X is O, m is 0 and p is 2, the following (1) and (2) are excluded: (1) n is 2 and B is 3,4-dimethylphenyl, 4-t-butylphenyl, 4-(t-butyl-CH2C(CH3)2)phenyl, 4-isopentylphenyl, 2-isopropyl-5-methylphenyl, 3-methoxyphenyl or 2-Cl-4-Br-phenyl, (2) n is 3 and B is 2,6-dimethylphenyl, phamaceutically acceptable salt, prodrug, or hydrate thereof.
(15) The compound described in above (14) excluding that X is O; m is 0; n is 2 or 3; p is 2; B is (a); one or two of R1, R2 and R3 is lower alkyl and the other is hydrogen.
(16) The compound described in above (14) excluding a compound wherein X is O; m is 0; n is 2; p is 2; B is (a); R1 is lower alkoxy, R2 and R3 are hydrogens.
(17) The compound described in any one of above (14) to (16) wherein B is (a) or (e).
(18) The compound described in any one of above (14) to (16) wherein R1 is halogen; R2 and R3 are each independently hydrogen, halogen or lower alkyl.
(19) The compound described in above (18) wherein R1 is halogen; R2 and R3 are each independently hydrogen or halogen.
(20) The compound described in any one of above (14) to (16) wherein R1 is halogenated lower alkyl, R2 is hydrogen or halogenated lower alkyl, R3 is hydrogen.
(21) The compound described in any one of above (14) to (16) wherein X is O or NR wherein R is methyl or ethyl.
(22) The compound described in above (21) wherein X is O.
(23) The compound described in any one of above (14) to (16) wherein m is 0.
(24) The compound described in any one of above (14) to (16) wherein n is 2 or 3.
(25) The compound described in above (24) wherein p is 2.
(26) The compound described in above (14) wherein B is (a) and R1 is halogen, R2 and R3 are each independently hydrogen, halogen or lower alkyl; X is O; m is 0; n is 3; p is 2.
(27) The compound described in above (26) wherein B is (a) and R1 is halogen; R2 and R3 are each independently hydrogen or halogen; X is O; m is 0; n is 3; p is 2.
(28) The compound described in above (14) wherein B is (a) and R1 is halogenated lower alkyl, R2 is hydrogen or halogenated lower alkyl, R3 is hydrogen, X is O; m is 0; n is 3; p is 2.
(29) A pharmaceutical composition containing a compound described in any one of above (14) to (28).
(30) A composition for use as an antiobestic agent containing a compound described in any one of above (14) to (28).
(31) A composition for use as a preventive or therapeutic agent for diabetes containing a compound described in any one of above (14) to (28).
(32) A composition for use as an agent for increasing concentration of leptin in blood, containing a compound described in any one of above (14) to (28).
(33) A method for preventing or treating obese, which comprises administering a compound described in any one of above (1) to (11) or (14) to (28).
(34) A method for preventing or treating diabetes, which comprises administering a compound described in any one of above (1) to (11) or (14) to (28).
(35) A method for increasing concentration of leptin in blood, which comprises administering a compound described in any one of above (1) to (11) or (14) to (28).
(36) Use of a compound described in any one of above (1) to (11) or (14) to (28) for production of an antiobestic agent.
(37) Use of a compound described in any one of above (1) to (11) or (14) to (28) for production of a preventive or therapeutic agent for diabetes mellitus.
(38) Use of a compound described in any one of above (1) to (11) or (14) to (28) for production of an agent for increasing concentration of leptin in blood.
One of the structural features of compound (I) is to have an unsaturated 5- to 7-membered, preferably 6-membered cyclic amine.
Terms used herein are explained below. Unless otherwise mentioned, each term, by itself or as part of another, has the following meaning.
Examples of lower alkyl include a straight or branched C1 to C6 alkyl such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, neo-pentyl, tert-pentyl, n-hexyl, and the like and preferred is C1 to C4 alkyl, more preferred is methyl or ethyl.
Lower alkoxy includes oxy connected with the above lower alkyl, such as methoxy, ethoxy, i-propoxy, tert-butoxy, pentyloxy, hexyloxy and the like.
Halogen means F, Cl, Br and I.
Halogenated lower alkyl is preferably trihalogenated methyl (e.g., xe2x80x94CF3) and the like.
Halogenated lower alkoxy is preferably trihalogenated methoxy (e.g., xe2x80x94OCF3) and the like.
Aryl means a monocyclic or fused aromatic hydrocarbon group such as phenyl, xcex1-naphthyl, xcex2-naphthyl, anthoryl, indenyl, phenantryl and the like and preferred is phenyl.
Heteroaryl means an aromatic monocyclic or polycyclic group containing the same or different hetero atom selected from O, S and N.
The monocyclic group includes a 5- to 6-membered cyclic group containing one to four hetero atom, such as pyridyl, furyl, thienyl, tetrazolyl, pyrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thiaziazolyl, oxazinyl, triazinyl and the like and preferably pyridyl (e.g., 2-pyridyl), furyl (e.g., 2-furyl) or thienyl (e.g., 2-thienyl).
The polycyclic group includes a 2- or 3-cyclic hetero cyclic group containing one to five hetero atom and preferred is a 8- to 14-membered cyclic group such as quinolyl, isoquinolyl, indoryl, benzoimidazolyl, indazolyl, indorydinyl, benzofuryl, benzothienyl, acrydinyl, phenanthrydinyl and the like, and preferably quinolyl (e.g., 4-quinolyl), isoquinolyl (e.g., 5-isoquinolyl), benzothienyl (e.g., 5-benzothienyl), benzofuryl (e.g., 5-benzofuryl).
When the above aryl or heteroaryl is substituted, examples of the substituent include a same or different group selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower alkylthio, hydroxy, amino, carboxy, cyano, nitro, lower alkylcarbonyl, lower alkoxycarbonyl, halogenated lower alkyl, halogenated lower alkoxy, pyperidyl (lower) alkyl, carboxy (lower) alkoxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted aryl (lower) alkoxy and the like. These may be located at any substitutable position in a range of one to five, preferably one to three. Furthermore, as each substituent of the optionally substituted aryl, the optionally substituted aryloxy and the optionally substituted aryl (lower) alkoxy, exemplified are lower alkyl, halogen, halogenated lower alkyl, halogenated lower alkoxy and the like.
A is preferably the group exemplified by (a) to (e) in the above B, e.g., optionally substituted phenyl, optionally substituted pyridyl, optionally substituted isoquinolyl, optionally substituted quinolyl, optionally substituted thienyl, optionally substituted furyl, optionally substituted benzothienyl, or optionally substituted benzofuryl. More preferable group is optionally substituted phenyl (substituent: same or different, one to three group selected from the group consisting of halogen, hydroxy, lower alkyl (e.g., methyl, t-Bu), halogenated lower alkyl (e.g., xe2x80x94CF3), piperidyl (lower) alkyl (e.g., 1-piperidylmethyl), lower alkoxy (e.g., methoxy), halogenated lower alkoxy (e.g., xe2x80x94OCF3), carboxy lower alkoxy (e.g., carboxy methyl), optionally substituted aryl (e.g., optionally substituted phenyl (substituent: p-Br)), optionally substituted aryloxy (e.g., optionally substituted phenyl (substituent: trihalogenated lower alkyl (e.g., xe2x80x94CF3))), and optionally substituted aryl (lower) alkoxy (e.g., optionally substituted benzyl oxy (substituent: halogen (e.g., F), lower alkyl (e.g., methyl), trihalogenated lower alkyl (e.g., xe2x80x94CF3))).
X is preferably O or NR wherein R is methyl or ethyl, more preferably O.
m is preferably 0.
n is preferably 1xcx9c4, more preferably 3.
p is preferably 2.
The compound (I) includes a new compound, typically the compound (II).
A preferable bond form of each group (a) to (e), defined as B of compound (II) is shown below. 
B is preferably a group of (a), more preferably a group of (axe2x80x2). Z1 is preferably CH and R1 is preferably halogen, R2 and R3 are each preferably independently hydrogen or halogen. More preferably, R1 and R2 are halogen in meta and para positions (esp., Cl), R3 is hydrogen. When Z1 is CH, Z1 may be substituted by each of R1, R2 and R3. As the other preferable embodiment of (axe2x80x2), exemplified is a compound wherein Z1 is CH, R2 is hydrogen, R1 is a group selected from the group consisting of hydrogen, halogen (e.g., F, Cl, Br), lower alkyl (e.g., methyl, tert-butyl), lower alkoxy (e.g., methoxy) and halogenated lower alkoxy (e.g., CF3), which is substituted at the 2- or 3-position), R3 is optionally substituted phenyloxy wherein the substituent is same or different, one or two groups selected from the group consisting of hydrogen, halogen (e.g., F, Cl, Br), lower alkyl (e.g., methyl, tert-butyl), lower alkoxy (e.g., methoxy), and halogenated lower alkoxy (e.g., CF3), which may be substituted at any of 2- to 6-position.).
One of preferable embodiments of the compound (II) includes that wherein p=2, n=3, X=O, m=0, B=(axe2x80x2), R2=hydrogen and R3=optionally substituted phenyloxy such as compounds shown by formula (IIa) in Example 52. The compound (II) hereinafter, included in the scope of compound (I), may be referred to as compound (I).
The preparation of the compound (I) is exemplified below and the compound (II) can be prepared likewise. 
wherein, Y1 is a leaving group such as halogen, the other symbols are the same meaning as described above.
The compound (III) and the compound (IV) are reacted, if necessary in the presence of a base, to give the compound (I). As the base, carbonate (K2CO3, Na2CO3 and the like), NaOH, tertiary amine and the like can be used. Furthermore, KI may be used together with them. As a solvent, CH3CN, dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like can be used. The reaction temperature is usually about 10 to 200xc2x0 C., preferably room temperature to about 110xc2x0 C., reaction time is several hours to several ten hours, preferably about one to 20 hours, more preferably about 3 to 15 hours. The compound (III) and the compound (IV) are prepared by known reactions or may be commercially available products. 
wherein Y2 is halogen or the like, Y3 is hydrogen in the case of X=O, S or a leaving group (e.g., halogen, xe2x80x94COCF3 and the like), in the case of X=NR, the other symbols are the same meaning as described above.
The compound (V) and the compound (VI) are reacted, if necessary in the presence of a base, to give the compound (I). As the base, carbonate (K2CO3, Na2CO3 and the like), NaOH, tertiary amine and the like can be used. Moreover, KI may be used together with them. As a solvent, CH3CN, dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like can be used. The reaction temperature is usually about 10 to 200xc2x0 C., preferably room temperature to about 110xc2x0 C. The reaction time is several hours to several ten hours, preferably about 1 to 20 hours, more preferably about 3 to 15 hours. The compound (V) and the compound (VI) are prepared by known reactions or may be commercially available products.
Prior to the above each reaction, a functional group may be protected by a method well known to skilled persons and if necessary deprotected after the reaction.
Examples of the pharmaceutically acceptable salt of compound (I) include salts formed with inorganic bases, ammonia, organic bases, inorganic acids, organic acids, basic amino acids, halogen ions or the like, and inner molecular salts. Examples of the inorganic base include alkaline metal (e.g., Na, K) and alkaline earth metal (e.g., Ca, Mg). Examples of the organic base include trimethylamine, triethylamine, choline, procaine, ethanol amine and the like. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid and the like. Examples of the organic acid include p-toluene sulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid and maleic acid and the like. Examples of the basic amino acid include lysine, arginine, ornithine, histidine and the like.
Compound (I) May be Hydrate.
Prodrug means a derivative of the present invention compound, which has a chemically or metabolically decomposable group and is converted, by solvolysis or under physiological conditions, to a compound of present invention which is pharmaceutically active in vivo. A preparation of an appropriate prodrug-derivative is described in, e.g., Design of Pro agents Elsevier, Amsterdam 1985. When the compound of present invention has a carboxy group, examples of the prodrug include an ester derivative prepared by reacting a proper alcohol with an original acidic compound or an amide derivative prepared by reacting a proper amine with an original acidic compound. When the compound of present invention has a hydroxyl group, examples of the prodrug include an acyloxy derivative prepared by reacting a proper acylharide or a proper acidic anhydrate with a hydroxyl group-containing compound. When the compound of present invention has an amino group, examples of prodrug include an amide derivative prepared by reacting a proper acidic haloganated compound or a proper mixed acidic anhydrate with an amino group-containing compound.
The present compound can be administered orally or parenterally to animal including man as a pharmaceutical composition, especially antiobestic agent or preventive or therapeutic agent for diabetes. Examples of the administered form include granules, tablets, capsules, injections and the like. In formulation, various additives can be used such as excipients, disingrators, binders, lubricants, stabilizers, coloring agents, coating agents if necessary. Although the dosage of the compound of the present invention may vary depending on the age, weight, conditions of the patient, and the administration route and the like, the daily dose for adult can generally be about 20 to 1000 mg for oral administration. For parenteral administration, the daily dose can be about 2 to 10 mg.
As the present compound increases remarkably the concentration of leptin in blood, the preventive and therapeutic effect against various diseases associated with leptin is expected. According to recent study, it is known that leptin activates sympathetic nerve to decompose lipid in the obesity cells. Moreover, it is reported that if leptin concentration rises, the resistance of insulin is improved to the lower insulin concentration. From these results, it is suggested that the present compound and the agent for increasing the concentration of leptin containing the present compound is for use as an antiobestic agent and/or a preventive and therapeutic agent for diabetes mellitus. A more preferable compound of present invention shows potent anti-obesitic effect without repressing feeding deterrent excessively.